CH638510A5 - PROSTACYCLINANALOGA. - Google Patents

Description

40 The invention relates to new structural and pharmacological analogues of prostacyclin (PGI2) and 5,6-dihydroprosta-cyclin (PGIi), in particular prostacyclin-like compounds in which an endocyclic double bond is present from C-6 to C-7.

45 Prostacyclin is a compound endogenously formed in mammalian species that is structurally and biosynthetically related to prostaglandins (PG's). Prostacyclin has the following structural formula and atom numbering:

50

1

C00H

wherein R21 and R22 have the meaning given above,

(c) a carbonylamino radical of the formula -NR23COR21, in which R23 represents hydrogen or an alkyl radical having 1 to 4 carbon atoms and R2) have the meaning given above, or

(d) a sulfonylamino radical of the formula -NR23S02R21, in which R21 and R23 have the meaning given above, or

(e) a hydrazino radical of the formula -NR23R24, in which R23 has the meaning given above and R24 represents an amino radical of the formula -NR21R22 of the definition given above or a cycloamino radical of the definition given, and

The 5,6-dihydroprostacyclin has the following structural formula and atom numbering:

5 638 510

The molecules of prostacyclin and the new, asymmetric prostacyclin analogues according to the invention each have several centers of asymmetry and can be in racemic (optically inactive) form and in two enantiomeric (optically active) forms, i.e. right-handed and left-handed shapes. As shown, the pro-stacycline formula corresponds to the prostaglandin produced endogenously in mammalian tissue. In particular, reference is made to the stereo configuration at C-8 (a), C-9 (a), C-II (a), and C-12 (ß) of endogenously formed prostacyclin. The mirror image of the prostacyclin formula given corresponds to the other enantiomer. The racemic prostacyclin forms contain an equal number. A consideration of the formulas I and II shows that prostacy- both enantiomeric molecules, so that the given formula I clin and 5,6-dihydroprostacyclin (PG ^) are necessary in structural terms and their mirror image, to correctly reflect the corresponding racemic hung to PGF2a, the following structural formula and atomic number-15 prostacyclin.

For convenience, the use of the term "prostaglandin" ("PG") or "prostacyclin" ("PGI2") means the optically active form of prostaglandin or prostacyclin. Reference is made to the same absolute configuration as that of PGF2o obtained from mammalian tissue.

[The expression “prostaglandin-like” or “prostacyclinar-like” (PG-like or PGI-like) product refers here and in the following to all described monocyclic 25 and bicyclic cyclopentane derivatives, which are in at least one pharmacological field of application, which also includes the prostaglandins or the prostacyclin as effective. With regard to the formula III, prostacyclin and 5,6- may have been used. Dihydroprostacyclin trivial as a derivative of PGF-like compound. The formulas shown that

be designated. Prostacyclin, tri-stacycline-like product or a product vial that can be recycled as 9-deoxy-6,9cx-epoxy- (5Z) -5,6-didehydro-PGF1 and an intermediate product, 6-Dihydroprostacyclin as 9-deoxy-6,9a-epoxy-PGF1- stereoisomers of prostaglandin or prostacyclin-like proeding. With regard to the description of the product used, which has the same relative stereochemical configuration as tric stereoisomerism, Blackwood and co-workers have the corresponding prostaglan-in "Journal of the American Chemical Society", volume 90, page 35 din or prostacyclin obtained from mammalian tissue, or the special stereoisomer 509 (1968). Regarding a description of the product of the intermediate which can be used in the production of the above-mentioned stacyclins and its structural identification, John stereoisomers of the prostaglandin or prostacyclin-like son and coworkers in «Prostaglandins», volume 12, page 915 products are used again .

(1976). The term “prostacyclin analogs” is used here and in the following

For convenience, the new prostacyclin analogs described here and below for the stereoisomer of a prostacyclin-like gene are described according to the product that has the same relative stereochemical configuration recognized in the art as trivial no- prostacyclin obtained from mammalian tissue, or the prosthetic cycline system from N.A. Nelson used his enantiomers in “Jour- a mixture with the stereoisomer in question and des-nal of Médicinal Chemistry”, volume 17, page 911 (1974). Especially if in the sign. Consequently, all of the new prostacyclin 45 traps will have a formula for rendering a prostacyclin vate as 9-deoxy-PGF-like compounds or other and like product, the term “prostacy” preferably refers to PGIr or PGI2 derivatives. clinanaloges »to a compound of the formula in question

In the formulas given and those which follow, or show a mixture of the compound in question and its dashed lines on any rings in a-configura- enantiomers.

tion (i.e. below the level of the ring in question) - 50 In addition to the literature describing prostacyclin, the substituents are given. Solid lines at any one other reference by C. Pase-Asiak and L.S. Wol rings indicate in ß-configuration (above the level of the fe ("Biochem.", Volume 10, page 3657 (1971)), in which the relevant rings) hanging substituents. Wavy lines of positional isomers of prostacyclin, namely 7,8-dide - (-) indicate that the corresponding substituents hydro-PGIj and 8,9-didehydro-PGIx are described. One is present either in the a or β configuration or as a mixture of 55 further position isomers of prostacyclin, namely trans-4,5-cx and β configuration. Didehydro-PGl !, is from Nicolaou and co-workers in «J.C.S.

The side chain hydroxy residue on the C-15 in the stated former Comm. », 1977, pages 331 to 332 and Corey and Mitar formulas can be found according to the Cahn-Ingold Prelogue in« JACS », volume 99, pages 2006 to 2008 (1977) sequence rules in S or R configuration (cf. "J. Chem. Ed."). These three positional isomers are shown in volume 41, page 16, (1964)). Furthermore, on «Nature», volume 212, 60 de structural formulas:

Page 38 (1966). There is a discussion on the stereochemistry of prostaglandins. This discussion also applies to the new prostacyclin analogs according to the invention. Terms such as C-2, C-15 and the like refer to the carbon atom in prostaglandin or prostacyclin 65 analogue, which in position corresponds to the position of the same number in PGF2 (I or prostacyclin (cf.

ne numbering). HO in ration:

comes to stand.

638 510

6

.COOH

/

HO and

COOH

/ i

HO OH

The invention relates to prostacyclin analogs of the formula:

Z1-X2

Y ^ Y.-C-C-Ry i «i

R1 8 H5

in which mean:

Zx (1) - (CH2) g- (CH2) 2-CH2- or (2) - (CH 2) g- (CH2) 2-CF2-, where g = 1, 2 or 3;

Rlg is a hydrogen atom, an alkanoyloxy radical with 2 to 8 carbon atoms or an alkanoyloxymethyl radical with 2 to 8 carbon atoms inclusive;

Yj (1) trans-CH = CH—,

(2) cis-CH = CH,

(3) -CH2CH2— or

(4) -CsC;

M5 R5 ÖR12 or R5 OR12,

wherein R5 represents a hydrogen atom or the methyl radical and R12 represents an alkanoyl radical having 2 to 8 carbon atoms;

Lj R3 R4i R3 R4 or a mixture of ^

R3 R4 and R3 R4,

wherein R3 and R4, which may be the same or different, can represent hydrogen or fluorine atoms or methyl radicals, it being true that one of the radicals R3 and R4 only represents a fluorine atom if the other represents hydrogen or fluorine;

X2 (1) a radical of the formula -COOR2, in which R2 is an alkyl radical with 1 to 12 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical, one with 1, 2 or 3

Chlorine atom (s) or alkyl radical (s) with 1 to 3 carbon atom (s) substituted phenyl radical, one in the p-position by a radical of the formulas:

O

II

(a) —NH-CR25

O

II

(b) -0-C-R26 O

(c) -0-C - ^) - R27or

O

II

(d) -CH = N-NHC-NH2

in which R25 represents a methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH2 radical, R26 represents a methyl, phenyl, -NH2 or methoxy radical and R27 represents hydrogen, an acetamido radical, a substituted phenyl radical, a phenacyl residue, ie a remainder of the formula:

O

-ch2-c -TS, one in the p-position by a chlorine or

Bromine or a phenyl or benzamido substituted phenacyl radical;

O

II

(2) a radical of the formula -CH2OC-CpH2p-CH3, where p = 0.1,2,3,4,5 or 6,

(3) a radical of the formula -CH2NL2L3, in which L2 and L3 represent hydrogen atoms or alkyl radicals having 1 to 4 carbon atoms inclusive, or

(4) a radical of the formula -COL4, in which L4

(a) an amino radical of the formula -NR21R22, wherein R21 and R22 are

(1) hydrogen atoms,

(2) alkyl radicals with 1 to 12 carbon atoms,

(3) cycloalkyl radicals with 3 to 10 carbon atoms,

(4) aralkyl radicals with 7 to 12 carbon atoms,

(5) phenyl residues,

(6) phenyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxyl radicals, carboxy radicals, alkoxycarbonyl radicals with 1 to 4 carbon atoms or nitro radicals,

(7) carboxyalkyl radicals having 1 to 4 carbon atoms,

(8) carbamoylalkyl radicals having 1 to 4 carbon atoms,

(9) cyanoalkyl radicals with 1 to 4 carbon atoms,

(10) acetylalkyl radicals having 1 to 4 carbon atoms,

(11) benzoylalkyl radicals having 1 to 4 carbon atoms,

(12) benzoylalkyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals, alkoxy radicals with 1 to 3 carbon atoms, carboxy radicals, alkoxycarbonyl radicals with 1 to 4 carbon atoms or nitro radicals,

(13) pyridyl residues,

(14) pyridyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

638 510

(15) pyridylalkyl radicals having 1 to 4 carbon atoms,

(16) pyridylalkyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals or alkoxy radicals with 1 to 3 carbon atoms,

(17) hydroxyalkyl radicals having 1 to 4 carbon atoms,

(18) Dihydroxyalkyl radicals with 1 to 4 carbon atoms or

(19) are trihydroxyalkyl radicals having 1 to 4 carbon atoms, and it is true that at most one of the radicals R21 and R22 represents a radical other than a hydrogen atom or an alkyl radical,

(b) a cycloamino radical of the formulas:

in which R21 and R22 have the meaning given,

(c) a carbonylamino radical of the formula -NR23COR21, in which R23 represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and R21 has the meaning given,

(d) a sulfonylamino radical of the formula -NR23S02R21, in which R2I and R23 have the meaning given, or

(e) a hydrazine radical of the formula -NR23R24, in which R23 has the meaning given and R24 represents an amino radical of the formula -NR21R22 of the definition given or a cycloamino radical of the definition given, and

R7 (1) - (CH2) m-CH3,

in which mean:

m is an integer from 1 to 5;

h is 0 or an integer from 1 to 3;

sO, 1,2 or 3 and

T is a chlorine or fluorine atom or a trifluoromethyl. Alkyl with 1 to 3 carbon atoms or alkoxy with 1

3 carbon atoms, whereby it applies that at most two radicals T stand for radicals other than alkyl radicals.

The invention further relates to prostacyclin analogs of the formula:

15 in which Yx, Zh L: and R7 have the meaning given, Xj (1) for a radical of the formula -COOR10, in which R10 corresponds to the radical R2 or represents a hydrogen atom or a pharmacologically acceptable cation,

(2) a radical of the formula -CH2OH,

20 (3) a radical of the formula -CT ^ NL ^ Lj, in which and L3 have the meaning given, or (4) a radical of the formula -COL4, in which L4 has the meaning given,

Mx for a remainder of the formulas:

25th

/ \ / 's

R5 OH or R5 OH

wherein R5 is a hydrogen atom or a Q-Q-alkyl radical, 30 preferably a methyl radical, and

Rg represents a hydrogen atom or a hydroxyl or hydroxymethyl radical.

Because of their endocyclic double bond, the new prostacyclin analogs of the formulas given are all referred to as 6,7-didehydro-PGIi-like compounds. The new compounds of the formulas according to the invention in which Zx is (CH2) g- (CH2) 2-CF2- are referred to as 2,2-difluoro-PGIj-like compounds. If g = 2 or 3, the new 40 compounds according to the invention are additionally referred to as 2a-homo-PGI1-like or 2a, 2b-dihomo-PGI1-like compounds. In this case, the additional methylene or ethylene residue is considered for nomenclature purposes as if it had been inserted between the carbon atoms C-2 and C-3. Furthermore, such additional carbon atoms from C-2 to C-3 are counted as C-2a and C-2b.

The new prostacyclin analogs according to the invention, in which Rs represents a hydrogen atom or a hydroxymethyl radical, are referred to as 11-deoxy-PGII or 11-deoxy-II-50 hydroxymethyl-PGII-like compounds. In addition, when Yj is cis-CH = CH-, -CH2CH2- or -C = C-, the new compounds are called 13-cis-PGIi-, 13,14-dihydro-PGIp or 13,14-didehydro- PGIj-like connections.

55 Those new compounds of the formula given according to the invention in which Mt has the formulas:

/ 'S / •' S

R5 OH or R5 OH

60

corresponds and R5 is preferably a methyl radical, are referred to as 15-methyl-PGIj-like compounds.

With the exception of the 13-cis-PGIj-like compounds described, all of the described compounds 65 with a hydroxyl radical in the β configuration at the C-15 are additionally referred to as 15-epi-PGIx-like compounds. Of the 13-cis-PGIj-like compounds according to the invention, only those with a hydroxyl radical in the a configuration are used

638 510

at C-15 referred to as 15-epi-PGI-like compounds. The basis for this nomenclature system with regard to the natural and epimeric configurations on the C-15 results from US Pat. No. 4,016,184.

If R7 is a radical of the formula - (CH2) m-CH3 with m in the definition given, the novel compounds according to the invention are called 19,20-Dinor-PGIj-, 20-Nor-PGIr, 20-methyl-PGIr or Designated 20-ethyl-PGIj-like compounds when m = 1, 2, 4 or 5.

If R7 for a remainder of the formula:

- <y

(T).

/

(T).

where T and s have the meanings given and none of the radicals R3 and R4 represents a methyl radical, the new compounds according to the invention are referred to as 16-phenyl-17,18,19,20-tetranor-PGIi-like compounds, provided s = 0 If s = 1, 2 or 3, the corresponding compounds are referred to as 16- (substituted phenyl) -17,18,19,20-tetra-nor-PGI-like compounds. If one and only one of the radicals R3 and R4 represents a methyl radical or both radicals R3 and R4 stand for methyl radicals, then the corresponding compounds with R7 in the previously defined meaning are designated as 16-phenyl- or 16- (substituted-substituted phenyl) -18,19,20-trinor-PGI1-, 16-methyl-16-phenyl- or 16-methyl- or 16- (substituted phenyl) -18,19,20-tri-nor-PGIj-like compounds.

If R7 for a remainder of the formula:

"CH;

/

(T).

where T and s have the meaning given, the new compounds according to the invention are referred to as 17-phenyl-18,19,20-trinor-PGIj-like compounds, provided s = 0. If s = 1,2 or 3, the corresponding compounds referred to as 17- (substituted phenyl) -18,19,20-trinor-PGI1-like compounds.

If R7 for a remainder of the formula:

(CH2)

(ZT

(T).

where T and s have the meaning given, the new compounds according to the invention are referred to as 18-phenyI-19,20-dinor-PGIi-like compounds, provided s = 0. If s = 1, 2 or 3, the corresponding compounds referred to as 18- (substituted phenyl) -19,20-dinor-PGI1-like compounds.

If R7 for a remainder of the formula:

(T)

where T and s have the meaning given, the new compounds according to the invention are referred to as 19-phenyl-20-nor-PGIj-like compounds, provided s = 0. If s = 1, 2 or 3, the corresponding compounds are shown as 19 - (Substituted phenyl) -20-nor-PGIrlike compounds.

If R7 for a remainder of the formula:

5 with T and s has the meaning given and none of the radicals R3 and R4 represents a methyl radical, the new compounds according to the invention are referred to as 16-phenoxy-17,18,19, 20-tetranor-PGIi-like compounds, provided s = 0. If s = 1, 2 or 3, the corresponding io compounds are referred to as 16- (substituted phenoxy) -17,18,19,20-tetranor-PGIj-like compounds. If one and only one of the radicals R3 and R4 represents a methyl radical or both radicals R3 and R4 stand for methyl radicals, then the corresponding compounds with R7 in the definition given shortly before are given as 16-phenoxy- or 16- (substituted phenoxy) -18,19,20-trinor-PGIj-, 16-methyl-16-phenoxy- or 16- (substituted phenoxy) -18,19,20-tri-nor-PGIi-like compounds.

If at least one of the radicals R3 and R4 has a different meaning than hydrogen, then (with the exception of the 16-phenoxy or 16-phenyl compounds already discussed) the compounds described in this way are called 16-methyl-PGI ^ -like (one and only one of the radicals R3 and R4 stands for a methyl radical), 16,16-dimethyl-PGIrike 25 (the radicals R3 and R4 both stand for methyl radicals), 16-fluoro-PGIi-like (one and only one of the radicals R3 and R4 stand for a fluorine atom) or 16,16-difluoro-PGIrartig (both residues R3 and R4 stand for fluorine atoms) compounds. Of those compounds in which the radicals R3 and R4 30 are different from one another, the corresponding prostaglandin analogs contain an asymmetric carbon atom at C-16, which is why two epimeric configurations are possible (16S) and (16R). The C-16 epimer mixture (16RS) also falls under the invention.

If a radical of the formula -CH2OH stands for, the new compounds according to the invention are referred to as 2-decarboxy-2-hydroxymethyl-PGIj-like compounds.

If Xj represents a radical of the formula -COL4, the new compounds according to the invention are referred to as PGI-like amides. If Xt furthermore represents a radical of the formula -COOR10, the new compounds according to the invention are referred to as PGIj-like esters or PGIi-like salts.

45 alkyl radicals with 1 to 12 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, no-nyl, decyl, undecyl or dodecyl radicals or their isomeric forms.

Examples of cycloalkyl radicals having 3 to 10 carbon-50 atoms are including alkyl-substituted cycloalkyl radicals cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2 -Methylcyclobutyl-, 3-propylcyclobutyl-, 2,3,4-triethyl-cyclobutyl-, cyclopentyl-, 2,2-dimethyl-cyclopentyl-, 2-pentyl-55 cyclopentyl-, 3-tert.-butylcyclopentyl-, cyclohexyl- , 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl residues.

Examples of aralkyl radicals with 7 to 12 carbon atoms 60 are benzyl, 2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (l-naphthylethyl) - and l- ( 2-naphthylmethyl) residues.

Examples of phenyl radicals substituted with 1 to 3 chlorine atoms or alkyl radicals with 1 to 4 carbon atoms are 65 p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m -Tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl residues.

9 638 510

Examples of radicals of the formula: thyl-, 2,4-dichlorobenzoylmethyl-, 2,4,6-trichlorobenzoylme-

thyl-, m-nitrobenzoylmethyl-, p-nitrobenzoylmethyl-, p-meth- (y) oxybenzoylmethyl-, 2,4-dimethoxybenzoylmethyl-, 3,4,5-tri-

s methoxybenzoylmethyl-, p-hydroxymethylbenzoylmethyl-,

5 p-Methylbenzoylmethyl-, m-methylbenzoylmethyl-, p-ethyl-benzoylmethyl-, tert-butylbenzoylmethyl-, p-carboxybenzoyl-methyl-, m-methoxycarbonylbenzoyl-, o-carboxybenzoylme-where T is an alkyl radical with 1 to 3 carbon atoms or ethyl, o-hydroxybenzoylmethyl, p-chlorobenzoylethyl, a fluorine or chlorine atom, a trifluoromethyl radical or an m-chlorobenzoylethyl, 2,4-dichlorobenzoylethyl, 2,4,6-tri-alkoxy radical having 1 to 3 carbon atoms stands and s = 0.1.2% chlorobenzoylethyl, m-nitrobenzoylethyl, p-nitrobenzoyl or 3, it being true that no more than two radicals T are another ethyl, p-methoxybenzoylethyl, p-ethoxybenzoylethyl, Having 2,4-meaning as alkyl radicals are phenyl, (o-, m- or dimethoxybenzoyl-ethyl-, 3,4,5-trimethoxybenzoyl-ethyl-, p-) - toyl-, (o-, m- or p-) ethylphenyl -, 2-Ethyl-p-tolyl, p-hydroxymethylbenzoylethyl, p-methylbenzoylethyl, m-Me

4-ethyl-o-tolyl-, 5-ethyl-m-tolyl-, (o-, m- or p-) propylphthalylbenzoylethyl-, p-ethylbenzoylethyl-, tert-butylbenzoyl-nyl-, 2-propyl- (o-, m- or p-) tolyl-, 4-isopropyl-2,6-xylyl-, 15-ethyl-, p-carboxybenzoylethyl-, m-methoxycarbonylbenzoyl-3-propyl-4-ethylphenyl-, (2,3 , 4-, 2,3,5-, 2,3,6- or 2,4,5-) triethyl, o-carboxybenzoylethyl, o-hydroxybenzoylethyl, methylphenyl, (o-, m- or p-) fluorophenyl-, 2-fluoro- (o-, m- p -chlorobenzoylpropyl-, m-chlorobenzoylpropyl-, 2,4-dichloro- or p- (tolyl-, 4-fluoro-2,5-xylyl-, (2,4-, 2,5-, 2,6-, 3,4- or benzoylpropyl-, 2,4,6-trichlorobenzoylpropyl, m-nitrobenzoyl-3,5-) difluorophenyl-, (o-, m- or p-) chlorophenyl-, 2-chloro-p-propyl-, p-nitrobenzoylpropyl-, p-methoxybenzoylpropyl-, tolyl-, (3-, 4-, 5- or 6-) chloro-o-tolyl-, 4 -Chlor-2-propylphe- 20 2,4-dimethoxybenzoylpropyl-, 3,4,5-trimethoxybenzoylpronyl-, 2-isopropyl-4-chlorophenyl-, 4-chloro-3,5-xylyl-, (2,3 -, pyl-, p-hydroxymethylbenzoylpropyl-, p-methylbenzoylpro-

2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyl-, 4-chloro-3-fluoropyl-, m-methylbenzoylpropyl-, p-ethylbenzoylpropyl-, tert .-phenyl-, (3- or 4-) chloro-2-fluorophenyl-, o-, m- or p-tri- butylbenzoylpropyl-, p-carboxybenzoylpropyl-, m-methoxy-fluoromethylphenyl-, (o-, m- or p-) methoxyphenyl-, (o-, m-carbonylbenzoylpropyl-, o-carboxybenzoylpropyl-, o-hydro- or p-) ethoxyphenyl-, (4- or 5-) chloro-2-methoxyphenyl- 25 oxybenzoylpropyl-, p -Chlorbenzoylbutyl-, m-chlorobenzoylbu and 2,4-dichloro (5- or 6-) methylphenyl residues. tyl-, 2,4-dichlorobenzoylbutyl, 2,4,6-trichlorobenzoylbutyl,

Examples of phenyl esters substituted in the p-position (Xj = m-nitrobenzoylmethyl, p-nitrobenzoylbutyl, p-methoxybene - COOR10, R10 = p-substituted phenyl) are p-acetamido-zoylbutyl-, 2,4-dimethoxybenzoylbutyl-, 3,4,5-trimethoxyben-phenyl-, p-benzamidophenyl-, p- (p-acetamidobenzamido) - zoylbutyl-, p-hydroxymethylbenzoylbutyl-, p-methylbenzoyl-phenyl-, p- (p-benzamidobenzamido) -phenyl-, p-amidocarbo-30 butyl-, m-methylbenzoylbutyl-, p-ethylbenzoylbutyl-, tert-Bu-nylamidophenyl-, p-acetylphenyl-, p-benzylphenyl-, p-amidotylbenzoylbutyl-, p-carboxybenzoylbutyl- Methoxycarbo-carbonylphenyl-, p-methoxycarbonylphenyl-, p-benzoyloxy- nylbenzoylbutyl-, o-carboxybenzoylbutyl- and o-hydroxyben-phenyl-, p- (p-acetamidobenzoyloxy) -phenyl- and p-hydroxy-. zoylmethylamide. Amides which fall under pyridylamino radicals, benzaldehyde semicarbazone esters. sjn (j a-pyridyl, ß-pyridyl and y-pyridylamide. Amides, the

Examples of the new prostacyclin 35 according to the invention which fall under substituted pyridylamino radicals are 4-methyl-a-amides (ie Xj = -COL4) are: pyridyl-, 4-methyl-β-pyridyl-, 4-chloro-a-pyridyl- and

(1) Amides, the alkylamino radicals of the formula -NR2iR22 4-chloro-ß-pyridylamide. Amides which fall under pyridylalkylaminoes, namely methyl, ethyl, n-propyl, n-butyl, n-pentyl, are a-pyridylmethyl-, β-pyridylmethyl-, y-pyri-n- Hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl-dylmethyl, a-pyridylethyl, ß-pyridylethyl, y-pyridylethyl, and n-dodecylamide as well their isomers. Further examples 40 a-pyridylpropyl-, ß-pyridylpropyl-, y-pyridylpropyl-, a-Py- are dimethyl-, diethyl-, di-n-propyl-, di-n-butyl-, methyl-ridylbutyl-, ß- Pyridylbutyl and y-pyridylbutylamide. Amides, ethyl-, methylpropyl-, methylbutyl-, ethylpropyl-, ethylbutyl- which fall under substituted pyridylalkylamino radicals are 4-Me- or propylbutylamide. Amides which come under cycloalkylamino residues thyl-a-pyridylmethyl-, 4-methyl-ß-pyridylmethyl-, 4-chloro-are cyclopropyl-, cyclobutyl-, cyclopentyl-, 2,3-dima-a-pyridylmethyl-, 4- Chloro-ß-pyridylmethyl-, 4-methyl-a-py-thylcyclopentyl-, 2,2-dimethylcyclopentyl-, 2-methylcyclopen- 45 ridylethyl-, 4-methyl-ß-pyridylethyl-, 4-chloro-a-pyridyl- tyl-, 3-tert-butylcyclopentyl-, cyclohexyl-, 4-tert-butylcy- ethyl-, 4-chloro-ß-pyridylethyl-, 4-methyl-a-pyridylpropyl-,

clohexyl-, 3-isopropylcyclohexyl-, 2,2-dimethylcyclohexyl-, 4-methyl-ß-pyridylpropyl-, 4-chloro-a-pyridylpropyl-, cycloheptyl-, cyclooctyl-, cyclononyl-, cyclodecyl-, N-methyl- 4 -Chlor-ß-pyridylpropyl-, 4-methyl-a-pyridylbutyl-, 4-Me-N-cyclobutyl-, N-methyl-N-cyclopentyl-, N-methyl-N-cyclothyl-ß-pyridylbutyl-, 4-chloro-a-pyridylbutyl- and 4-chloro-hexyl-, N-ethyl-N-cyclopentyl-, N-methyl-N-cyclohexyl-, di- so ß-pyridylbutylamide. Amides, the hydroxyalkylamino cyclopentyl, and dicyclohexylamide. Amides which come under aralkyl are hydroxymethyl, a-hydroxyethyl, β-hydroxy amino residues are benzyl, 2-phenylethyl, 1-phenylethyl, ethyl, a-hydroxypropyl, ß-hydroxypropyl , y-hydroxy-N-methyl-N-benzyl, and dibenzylamide. Amides which fall under sub-propyl, l- (hydroxymethyl) ethyl, l- (hydroxymethyl) -prostituted phenylamino radicals are p-chloro, m-chloro, py] .; (2-hydroxyethyl) propyl and a, a-dimethyl-ß-hydr-

2,4-dichloro, 2,4,6-trichloro, m-nitro, p-nitro, p-methoxy, 55 oxyethyl amide. Amides which fall under dihydroxyalkylamino residues fal-3,4-dimethoxy-, 3,4,5-trimethoxy-, p-hydroxymethyl-, p-meles are dihydroxymethyl-, a, a-dihydroxyethyl-, a, ß-di -thyl-, m-methyl-, p-ethyl-, tert-butyl-, p-carboxy-, p-meth-hydroxyethyl-, ß, ß-dihydroxyethyl-, cx, a-dihydroxypro-oxycarbonyl-, o- Carboxy and o-hydroxyanilide. Amides which fall un-pyl-, a, ß-dihydroxypropyl, a, y-dihydroxypropyl, ß, ß-carboxyalkylamino residues are carboxymethyl, carb-dihydroxypropyl, ß, y-dihydroxypropyl, y, y- Dihydroxy-oxyethyl, carboxypropyl and carboxybutylamide. Amides, the 60 propyl-, l- (hydroxymethyl) -2-hydroxyethyl-,

carbamoylalkylamino radicals include carbamoylme- l- (hydroxymethyl) -l-hydroxyethyl-, a, a-dihydroxybutyl-, thyl-, carbamoylethyl-, carbamoylpropyl- and carbamoylbu- a, ß-dihydroxybutyl-, a, y-dihydroxybutyl- a, ô-dihydr-tylamide. Amides which fall under cyanoalkylamino radicals are oxybutyl-, β, ß-dihydroxybutyl-, β, y-dihydroxybutyl-, cyanomethyl-, cyanoethyl, cyanopropyl- and cyanobutyl- ß, ö-dihydroxybutyl-, y, y-dihydroxybutyl- y, ô-dihydroxy amide. Amides which fall under benzoylalkylamino radicals are butyl-, ô, ô-dihydroxybutyl- and l, l-bis- (hydroxymethyl) -benzoylmethyl-, benzoylethyl-, benzoylpropyl- and benzoyl- ethylamide. Amides that fall under trihydroxyalkylamino residues, butylamide. Amides which fall under substituted benzoylalkylamines are tris (hydroxymethyl) methyl and 1,3-dihydroxy-2-hydr-st are p-chlorobenzoylmethyl-, m-chlorobenzoylme-oxymethylpropylamide.

638 510 10

(2) Amides that fall under cycloamino residues are pyrrolicardine infarcts and shocks are administered. For this dyl, piperidyl, morpholinyl, hexamethyleneiminyl, piperazi purpose, the compounds according to the invention can be syste-nyl, pyrrolinyl and 3,4-didehydropiperidinylamide. mixed, for example intravenous, subcutaneous, intramuscular and

(3) Amides which fall under carbonylamino residues of the formula in the form of sterile implants for long-term use - NR23COR2i are methylcarbonyl, ethyl carbonyl, s are sufficient. To achieve a quick response, i.e. Phenylcarbonyl, and benzylcarbonylamide. Amides which fall under, in particular in emergencies, the intravenous administration sulfonylamino residues of the formula -NR23S02R2i are preferred. Doses in the range of methylsulfonyl, ethylsulfonyl, phenylsulfonyl, p-tolylsulfonyl in a range from about 0.01 to about 10 mg / kg of body weight / day are usually given. Die and benzylsulfonylamide. exact dose depends on the age, weight and condition of the patient

(4) Hydrazides which fall under hydrazine residues are hydrients or animals and depend on the frequency of administration and azine, N-aminopiperidine, benzoylhydrazine, phenylhydrazine, the route of administration.

N-aminomorpholine, 2-hydroxyethyl hydrazine, methyl hydrazine, the preferred dosage of the verbin-2,2,2-hydroxyethyl hydrazine and p-carboxyphenyl hydrazine according to the invention. fertilize is the oral dosage. Compared to parenteral administration

The term "pharmacologically acceptable cation" routes of administration are also used to refer to other non-parenteral routes to those pharmacologically acceptable salts of the routes of administration, e.g. a buccal, rectal, or sublingual prescription of prostacyclin-like carboxylic acids, the more common - preferred. Oral forms of administration can also be used for prostaglandins. Be produced in such a conventional manner. These are pharmacologically acceptable salts, for example tablets, capsules and the like, in particular the salts of pharmacologically acceptable metal cation. These forms of administration are used 2 to 4 times a day, amine cations and quaternary ammonium cations. 20 ben. Doses in the range of about 0.05 have been found to be effective. In addition, the salts of basic amino to 100 mg / kg body weight / day have also been found to be effective.

nonacids, e.g. of arginine and lysine. Particularly good As in-vitro application area for the inventive amine cations, e.g. THAM [Tris compounds is the addition of the compounds in question

(hydroxymethyl) aminomethyl] and adamantanamine. Whole blood is also mentioned in the storage of whole blood, which is also to be used in heart / lungs in US Pat. No. 4,016,184, in particular columns 29, 25 machines. Furthermore, salts can be mentioned which are particularly suitable according to the invention. Whole blood containing compounds according to the invention

The new prostacyclin analogues according to the invention call organs, e.g. Hearts and kidneys, which give the donor a variety of biological reactions, which is why transplants have been taken, circulate in a wide variety of pharmacological applications. Finally, the connection areas according to the invention are suitable for use. Biological reactions also fertilize the production of platelet-rich concentrates are, in particular, an inhibition of a platelet aggregate for use in the treatment of thrombocytopenia, tion, stimulation of the smooth muscles, a reduction in chemotherapy and in radiation therapy. The do's of the blood pressure, a decrease in gastric juice secretion, when administered in vitro, usually ranges from 0.001 to an inhibition of by NOSAC (non-steroidal, ent-1.0 (ig / ml whole blood.

anti-inflammatory or anti-inflammatory compounds) induced ss pathological changes, a bronchodilatory effect- (b) smooth muscle stimulation:

kung, a nasal decongestation, a better blood circulation of the vessels which are peripheral to the new prostacyclin analogues according to the invention, a reproductive and fertility control may vigorously stimulate the smooth musculature and furthermore other known effects such as a change in the renal blood flow, a dermatosis mass Stimulators for smooth muscle regression, a reduction in inflammatory conditions and 40 kulatur, eg oxytocidal agents, such as oxytocin, and the various - a reduction in intraocular pressure. The most ergot alkaloids including their derivatives and

Consequently, the new prostacyclin analogs are suitable according to analogs. Thus, instead of or the invention, they are useful as a means of testing, preventing, in combination with less than usual amounts of these.

Control and treatment of diseases and other known stimulators for smooth muscles, for example undesirable physiological conditions in mammals, in particular for the relief of the symptoms of paralytic ileus, or for special people, valuable domesticated animals, home control or prevention of atonic uterine bleeding , zoological genera and species and laboratory - after an abortion or after birth, to support the animals (eg mice, rats, rabbits and monkeys). Ejection of the placenta and during the puerperium. For the latter purpose, the compound can be administered by intravenous infusion (a) inhibition of platelet aggregation: 50 sion immediately after abortion or birth in a

The new prostacyclin analogs according to the invention can be used in the range from about 0.01 to about 50 μg / kg body weight / s even if an inhalin is administered until the desired effect is achieved by platelet aggregation or a decrease occurs. Follow-up doses are preferably given by intravenous adhesive properties of the platelets or by elimination, subcutaneous or intramuscular injection or infusion or prevention of the formation of blood clots in mammals at the end of the week in an amount of 0.01 to 2 mg / kg People is desired. So these compounds can be administered body weight / day. The exact dose depends on the gene, for example in the treatment and to prevent the age, weight and condition of the patient or animal. of myocardial infarction, or to treat and prevent postoperative thrombosis, to improve the patency of vascular grafts after surgery - 60 (c) Lowering blood pressure:

and for the treatment of conditions such as atherosclerosis. The new prostacyclin analogs according to the invention are suitable

Atherosclerosis, blood clotting errors due to lipemia and also serve as hypotensive agents to lower blood-related clinical conditions in which the underlying pressure in mammals and humans. For this purpose, aetiology with a lipid imbalance or a hyperlipine which the compounds according to the invention are associated with by intravenous dememia can be given. Another in-line infusion at a rate of about 0.01 to about vivo is geriatrics. They can be administered at 50 [ig / kg body weight / min or in a single or multiple play elderly patients to prevent a cerebral dose of about 25 to 500 (xg / kg body weight / day) verishemic attacks and for long-term prophylaxis after myo.

11 638 510

As with the described antithrombic application, which is more known, for example according to a usual dosage regimen, the compounds according to the invention are also to be administered here, and are administered by an oral or other suitable non-parenteral route of administration.

Form administered. To determine the suitable oral Do- The prostacyclin analogue is usually together with the administration and frequency of administration, a titration of the Do- 5 anti-inflammatory or anti-inflammatory prostaglandin system in connection with other simultaneously administered anti-thetase inhibitor is required either by the same administration route hypertensive. Given alone as an antihy- or other route of administration. If the intensive agent is used to determine the required minimum dose, for example the anti-inflammatory or anti-inflammatory substance, for a suitable control of the blood pressure, the new prostacyclin analogue can also be administered or the therapy at or near the threshold dose of the 10 if oral or on the other hand begins rectally in the form of a suppository, patient or animal responsiveness. This is followed by or in women vaginally in the form of a suppository or an adjustment of the dosage upwards until a completely vaginally administrable form for slowly controlling the active ingredient has been reached or there are undesirable side effects (cf. US Pat. No. 3,545,439). If others hire. Usually threshold doses of the anti-inflammatory or anti-inflammatory substance are used rectally from 0.01 to 1.0 mg / kg body weight. 15 is administered, the new prostacyclin analog can also be administered rectally. Furthermore, the new prostacyclinan

(d) Reduction of gastric juice secretion: given in the usual way orally or vaginally in women

The new prostacyclin analogues according to the invention can. If the route of administration for both the inflamed

In mammals and humans, as well as certain substances that inhibit or inhibit value enhancement as well as for new animals, such as dogs and pigs, for the reduction and 20 prostacyclin analogues, it is particularly convenient to be given control of gastric juice secretion. To reduce both active ingredients to a single form of administration or avoid the formation of gastrointestinal.

nal ulcers and accelerate the healing of those already. The dosage instructions for the new prostacyclin analogue for ulcers present in the gastrointestinal tract. This treatment depends on a variety of factors,

For the purpose, the compounds according to the invention are preferred. the type, age, weight, sex, and wise injected or intravenously, subcutaneously or intramuscularly in the medical condition of the mammal or patient, which has an infusion dosage range of about 0.1 to about 20 µg / species and dosage regimen of the animal or infused humans at kg body weight / min. The anti-inflammatory or anti-inflammatory syn-

The total daily dose administered by fusion is generally sufficient for the thetaase inhibitor and the sensitivity of the particular dose to be administered.

from about 0.01 to about 10 mg / kg body weight / day. The sufficient prostacyclin analogues. For example,

The exact dose does not depend on the age, weight and condition of the patient - the same disadvantageous effects do not apply to every anti-inflammatory or anti-inflammatory animal or to the frequency of administration and the substance-taking people.

route of submission. strointestinal effects if the substance in question

However, the new prostacyclin analogs are preferably taken. In addition, the gastrointestinal gene according to the invention orally or on other non-parental effects often vary in their type and in their severity, teral route of administration. With oral administration, however, it is within the skill of the attending physician or animal, 1 to 6 administrations a day from about 1.0 to doctor to determine that the administration of the respective ent-100 mg / kg body weight / day is recommended. After the anti-inflammatory or anti-inflammatory substance in the patient has healed, the maintenance dose required to reduce a gastrointestinal side effect or recurrence of undesirable gastrointestinal effects is usually reduced by as much as 40 mft by an effective amount of the new prostacyclin analo-long. until the patient or animal prescribes the asymptomatic gene to minimize the effects in question. to eliminate that and afterwards completely.

(e) Inhibition of a pathological (f) bronchodilatory (antiasthmatic) effect induced by NOSAC: Change: 45 The new prostacyclin analogs according to the invention are

The new prostacyclin analogs according to the invention are also suitable for the treatment of asthma. Thus, the inventors can furthermore reduce the number of anti-inflammatory or anti-inflammatory gates or inhibitors of mediators, e.g., as a bronchodil administration, from a systematic compound. SRS-A, and hist-prostaglandin synthetase inhibitors originating from undesirable amine, which result from gastrointestinal effects activated by an antigen / antibody complex. For this purpose, the fourth cells are released and used. So offset e.g. by simultaneous administration of the prostaglandin, the compounds according to the invention therefore like spasms of derivatives and of the anti-inflammatory or anti-inflammatory products and breathing in conditions such as bronchial bronchitis, staglandin synthetase inhibitor (cf. US Pat. No. 3,781,429) in the bronchial hectasis, pneumonia and emphysema For this purpose, the anti-inflammatory or anti-inflammatory agents according to the invention are induced in rats and usually lead to 55 compounds in the most varied of administration ulcers by simultaneous oral administration forms. inhibited orally in the form of tablets, capsules or the administration of certain prostaglandins). Consequently, liquids, rectally in the form of suppositories, parenterally, are suitable for the new prostacyclin analogs according to the invention - subcutaneously or intramuscularly (with preference for intravenous dosing, for example, to reduce the need for systematic administration in emergencies) by inhalation in the form of administration of indomethacin, phenylbutazone and 60 of aerosols or solutions for nebulizers or aspirin, undesirable gastrointestinal effects resulting from blowing in the form of a powder. The cans te. The substances mentioned in US Pat. No. 3,781,429 generally range from about 0.01 to 5 mg / kg of body weight 1 — specifically as non-steroidal, anti-inflammatory or —with up to 4 times a day. The exact dose depends on age, weight drige means called. These compounds are also known to the patient and the condition of the administration and are known to be prostaglandin synthetase inhibitors. 65 and the route of administration. On this application

The anti-inflammatory or anti-inflammatory synthetase areas can advantageously inhibit the prostacyclin analogs, for example indomethacin, aspirin or phenylbu with other anti-asthmatic agents, e.g. Sympathomimetic

tazon, may be used to relieve inflammatory conditions (isoproterenol, phenylephrine, ephedrine and the like),

638 510

12

Xanthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone) can be combined.

The compounds of the invention can be effectively administered to asthmatics by oral inhalation or by inhalation of an aerosol. For administration by oral inhalation with conventional nebulizers or by oxygen aerosolization, it is customary to administer the active ingredient consisting of a compound according to the invention in dilute solution, preferably in a concentration of about 1 part of medicament to about 100 to 200 parts by weight of total solution. To stabilize these solutions or to generate isotonic media, conventional additives, e.g. Sodium chloride, sodium citrate, citric acid, sodium bisulfite and the like can be used. For administration as a self-propelled dosing unit, i.e. for administration of the active ingredient in an aerosol form suitable for inhalation therapy, the composition may contain the active ingredient suspended in an inert propellant (e.g. a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a cosolvent such as ethanol, a flavor or odorant and a stabilizer. Suitable measures for performing aerosol inhalation therapy are described in US Pat. No. 2,868,691.

(g) Nasal decongestation:

The new prostacyclin analogs according to the invention can be used in mammals and humans as nasal decongestants. For this purpose, doses are usually given from about 10 ng to about 10 mg / ml of a pharmacologically acceptable liquid carrier or as an aerosol spray, both for topical application.

(h) Improving the (blood) circulation in peripheral vessels:

The prostacyclin analogs according to the invention are also suitable for the treatment of peripheral vascular diseases in humans. The term "peripheral vascular diseases" includes here and below any diseases or pathological disorders of the blood vessels outside the heart and diseases or pathological disorders of the lymphatic vessels, e.g. Freezing bumps, ischemic cerebrovascular diseases, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venous weakness, gangrene, heptatorial syndromes, ductus arteriosus, non-obstructive, mesenteric ischemia, arteritis lymphangitis and the like. The diseases mentioned are only examples of peripheral vascular diseases. To correct such conditions, the prostacyclin analogs according to the invention can be administered orally or parenterally via a direct injection or infusion into a vein or artery. Intravenous or intraarterial injections are preferred. The preferred dosage for infusions by hourly administration or by injection 1 to 4 times a day ranges from 0.01 to 1.0 jig / kg body weight. The exact dose depends on the age, weight and condition of the patient and on the frequency and route of administration. Corresponding preferred oral doses are 0.05 to 50 mg every 2 hours with a maximum of 6 daily doses. Treatment can be continued for 1 to 5 days, although 3 days is usually sufficient to ensure long-term therapeutic effects. If systemic effects or side effects are observed, the dose can be reduced below the threshold at which such systemic effects or side effects are observed.

(i) Reproductive and fertility control:

The new prostacyclin analogues according to the invention can also replace oxytozine to induce labor in pregnant animals such as cows, sheep and pigs, or 5 pregnant women at or near the appointment or in pregnant animals with intrauterine death of the fetus from around the 20th week apply until the appointment. For this purpose, the respective connection at or near the end of the second stage of labor, i.e. when the fetus is expelled, infused intravenously at a dose of 0.01 to 50 fxg / kg body weight / min. The prostacyclin analogs according to the invention are particularly well suited for use in women who have been transmitting for one or more week (s) and who have not yet had natural contractions, 15 if 12 to 60 h after the rupture or tearing of the amniotic sac no natural ones Labor pains. Other preferred routes of administration are oral or other parenteral routes, e.g. an intramuscular administration.

The prostacyclin derivatives according to the invention can also be used to control the reproductive cycle in menstruating female mammals, including women. The term “menstruating female mammals” is to be understood as meaning animals that have already reached a level of maturity sufficient for menstruation, but which are not yet so old that normal menstruation has ceased. For this purpose, the compounds are usually administered systemically in a dose of 0.01 to about 20 mg / kg body weight (of the female mammal). The administration is expediently carried out during a time period beginning around the time of ovulation and ending around the time of the menses or shortly before the menses. Other preferred methods of administration are intravaginal and intrauterine administration. In addition, if the compound in question is administered similarly during the first or second trimester of normal mammalian or normal pregnancy, the embryo or fetus may be expelled.

The prostacyclin analogs according to the invention are furthermore suitable for inducing cervical dilatation in pregnant or non-pregnant female mammals for gynecological and obstetric purposes. Cervical dilation is also observed in labor and clinical abortion induced by these connections. In cases of infertility, the cervical dilation caused by these connections supports sperm movement to the uterus. Cervical dilation caused by these connections has also been found in surgical gynecology, e.g. D and C so (cervical dilation and uterine curettage), in which mechanical dilation can result in uterine perforations, cervical tears or infections, have been shown to be valuable. Furthermore, the prostacyclin analogs according to the invention are suitable for diagnostic purposes if a dilatation for tissue examination is required. For these purposes, the compounds according to the invention can be administered locally or systemically.

The prostacyclin analogs according to the invention are administered, for example, orally or vaginally in a dose of about 5 to 50 mg 60 per treatment of an adult woman at 1 to 5 doses per 24 hours. On the other hand, the prostacyclin analogs according to the invention can also be administered intramuscularly or subcutaneously in doses of approximately 1 to 25 mg per treatment. The exact dosage for these purposes depends on the age, weight and condition of the patient or animal.

Furthermore, the prostacyclin analogs according to the invention are suitable in domesticated animals (1) as abortives, in particular for (feedlot) heifers, (2) as aids for detecting the

13 638 510

Oestrus, (3) as a control means for the oestrus. As domesticated active ingredients) usually make up about 0.1 to about 15, animals are horses, cattle, sheep and pigs. The preferably about 0.5 to about 2% by weight of the drug control or synchronization of the oestrus enables one out. In addition to topical administration, the more effective monitoring of both the conception and the compounds according to the invention can be carried out using suitable contractions, in that the breeder can have all female animals multiplied intradermally, intra- or perilesi-ces, in short sterile saline bases . Can be injected intravenously or subcutaneously.

This synchronization leads to a higher percentage of live births than can be achieved by natural control (1) Reduction of inflammation:

that can. Such a synchronization is also suitable. The new prostacyclin analogs according to the invention are suitable

Particularly important for facilitating artificial insemination, "> continue to be anti-inflammatory or anti-inflammatory since the insemination processes can be made more economical means of inhibiting chronic inflammatory conditions. For this purpose, the mammals according to the invention can include swellings and other un-stacycline analogues in Doses of 0.1 to 100 mg per animal inject pleasant side effects of such inflammation.Here or with the food.You can combine the treatment methods and dosages with other agents, such as steroids, as you like U.S. Patent No. 3,885,041, the regimen of administration depends on the one to be treated

Species. For example, mares receive the reduction in intraocular pressure according to the invention:

Prostacyclin analogs 5 to 8 days after ovulation Finally, the new prostacyclin analogs are suitable

and becoming hot again. According to the invention, cattle can be treated in the same way in humans in order to reduce the origin, but afterwards, internal pressure can be increased in the case of disease states in which an abnormal additional administration is necessary in order to expediently increased pressure in the eye a danger to the eyesight wise to bring all cattle to a heat at the same time. of the patient, e.g. for glaucoma. Although numerous routes of administration are suitable for this purpose, direct application of a sterile ophthalmic solution provides (j) a change in the renal blood flow: for example in the form of drops, for reasons of convenience

The new prostacyclin analogs according to the invention, and with a view to the greatest possible reduction in the blood flow or flow in the kidneys of mammals, are the preferred route of administration. Although the volume to be increased and the electrolytes increase, the dose to be administered is ultimately given to humans by addressing the urine tene content. For this reason, the patients concerned (markedly reduced intraocular pressure and absent connections to remedy cases of kidney localized side effects, eg irritation of the dysfunction of the eyes, especially those in which a blockage can be determined) are recommended the kidney vascular bed is initially dosed. For example, the levels of about 0.05 to 50 mg per few drops of the sterile compounds are suitable for the relief and the ophthalmic solution 2 to 4 times a day.

Exercise of edema, for example from massive surfaces. The new prostacyclin analogues according to the invention

burns, and to monitor 35 people are in extremely surprising and unexpected white shocks. For these purposes, the compounds in question can be shown to be suitable for use on a wide variety of pharmacological fertilizers, preferably first by intravenous injection in areas, which is why they are used both as a phar dose of 10 to 1000 μg / kg body weight or by macological as well as structural analogues of prostacyclin intravenous infusion in a dose of 0.1 to 20 (xg / kg body weight. In addition, the new prostacy per weight / min are administered until the desired Ef- 4 <> clinanalogen according to The subsequent doses are preferably given as intravenous stability, which facilitates their formulation and their use as medicinal agents, intramuscular or subcutaneous injections or infusion agents. Finally, the new prostacyclin analanols are in the range of 0.05 According to the invention, up to 2 mg / kg of body weight / day is superior to prostacyclin therein, it is sufficient that they, wi e described as antithrombotic, antiasthmatic

45 see or anti-inflammatory or anti-inflammatory means for (k) dermatosis removal: can be used. This increased usability results

The new prostacyclin analogs according to the invention are also particularly suitable from the fact that the new prostacyclin anenes are furthermore suitable for the treatment of proliferating skin logs according to the invention, an increased effectiveness or se diseases in humans and domesticated animals, e.g. develop selectivity of the effect, which is why they have fewer undesirable side effects, basal and squamous cell carcinomas of the skin, in the case of delivery psoriasis, atopic dermatitis, non-specific dermatitis, use for one of the preferred pharmacological uses of primary irritant contact dermatitis, allergic contact dermatitis purposes, call lamellar.

Ichthyosis, epidermolytic hyperkeratosis, pre-malignant, Of the new prostacyclin analogs according to the invention, keratosis induced by sun exposure, non-malignant, certain compounds are due to their increased keratosis, acne and seborrheic dermatitis in humans 55 effectiveness, selectivity or other reasons and atopic dermatitis and mange domesticated animals particularly preferred. In particular, certain errors have occurred. The compounds according to the invention alleviate the symp bindings when used for the tome of these proliferating skin diseases which are preferred. Psoriasis has been shown to be particularly good and valuable for purposes of use, for example, to be regarded as relieved if a buff. Preferred compounds are those of the indicated pen-free psoriasis wound in their thickness or strength 00 formula, wherein Zt for - (CH2) g ~ (CH2) 2 -CH2 stands. Expediently decreases and noticeably, but still incompletely or in some cases, g stands for 1, 2 or 3, preferably for 1. With respect to what has become completely pure. of the rest Y1, those compounds of the specified

In these fields of application, the formula according to the invention in which Yj is trans-CH = CH-,

according to compounds as medicaments with a suitable -CH2CH2- or -C = C-, in particular trans-CH = CH-, pharmaceutical carrier, for example as an ointment, lotion, Pa-65.

ste, gel, spray or aerosol, and topical foundations, such as with respect to the rest of Lj, those compounds

Vaseline, lanolin, polyethylene glycols and alcohols, topically preferred the formula given, in which R3 and R4 are applied by diesel. The compounds according to the invention (are of importance. Furthermore, those compounds

638 510

14

io gene preferred, in which at least one of the radicals R3, R4 and R5 represents a hydrogen atom. In the event that Yx ice—

CH = CH- or -C = C-, those compounds of the formula given are preferred in which R3, R4 and R5 all represent hydrogen atoms.

Regarding m, h and s, m preferably = 3, h = 0 or 1 and s = 0 or 1. T preferably represents a chlorine or fluorine atom or a trifluoromethyl radical.

Other preferred compounds are the carboxylic acids or carboxylic acid derivatives, i.e. Esters, especially the p-substituted phenyl esters, and the amides. With regard to the new amides, preference is given to those compounds of the formula given in which R21 and R22, which may be the same or different, represent hydrogen atoms or alkyl radicals having 1 to 8 carbon atoms, preferably the total number of carbon atoms of the radicals R2i and R22 is less than or equal to 8. Those amides in which R21 and R22, which may be the same or different, for hydrogen atoms or alkyl radicals with 1 to 4> are particularly preferred

Are carbon atoms, the total carbon atom 20 R i ß number of the radicals R2i and R22 is less than or equal to 4. R23 preferably represents a hydrogen atom.

The reaction scheme given below explains the preferred method by which the new prostacyclin analogs according to the invention can be prepared from known or easily synthesized starting materials. In this reaction scheme, the parameters A, g,

Lls Mj, R7, R8, Xj, X2 and Z, the meaning given.

CH2- (CH2) n ~ ^ (R2) 2 ~ X2

XXIV

v

-C-R,

<x

CH2-C-CH2- (CH2) g-C (R2) 2.X2

-C C-R7

II II Ms Lj

XXV

Zi-X2

Reaction scheme

30th

HO

Rb

H\

lc = c

CH2 ^ -CH2- (CH2) -C (R2) 2-X3

Y1-C-R7

II I Mi Ii

35

XXI

v

* 1 8

I.

£ f a

XXVI

-c-II

Ms

■ R?

XXVII

Shark

S

45

Yi-C C-R7

II II Ml Li

* I

CH-CH2- (CH2) g-C (Rz) 2-X3

\ k y 2i "Xi

XXII

-C-R,

XXVIII

55

Yi-C

ii

M

C-R7

II

1 li

X-! means:

Shark

: H-CH2- (CH2) g-C {R2) 2-X2

R1 8

Y i-C C-R7

II II

M5 LJ

v

(1) a radical of the formula —COOR2, in which R2 has the meaning given;

60 (2) a residue of the formula -CH2OH;

(3) a residue of the formula -CTyStl ^ L ^; or VV17T (4) a radical of the formula -COL4, in which L4 is the one indicated

Has meaning.

X4 means:

65 (1) a radical of the formula -COORn, in which Rn represents an alkali metal cation;

(2) a residue of the formula -CH2OH;

(3) a residue of the formula -CH2NL2L3, wherein L2 and L3 are the

15 638 510

have the meaning given; or a similar conventional insulation method shown purely.

(4) a radical of the formula -COL4, wherein L4 is the specified one when undergoing a chromatographic product separation

Has meaning. served, care should be taken to ensure that no acidic

R2 represents a hydrogen or fluorine atom; Shark is used in particular aqueous acidic eluent. A bromine or iodine atom. 5 preferred eluent for this purpose is ethyl acetate in

The compounds of Skellysolve B indicated in the reaction scheme with a small amount, for example less

Formula XXI are either known or can be after 1%, an amine base such as triethylamine. Establish the described process. The compounds of the For-Isolierverfahren allows the separation of the desired mei XXI are PGF2u-like compounds in 6,7-didehydro-PGIj isomers of formula XXVI from others

Form of esters, amides, primary alcohols or amines, io impurities, mainly the corresponding PGI2-ar-

The compounds in question can all be made from light alkanoates.

available starting materials in a known manner - can be made from the compounds of formula XXVI. Dealcanoylation of prostacyclin analogs of Formula XXVII

The compounds of formula XXII are obtained e.g. received from the. For this purpose, one is used in particular

Compounds of formula XXI by halocyclization. If 15 alkali metal methoxide in methanol is used as the usual saponification

Hal corresponds to an iodine atom, this halocyclization takes place in medium. When the saponification is complete, the reac-

generally by reaction of the compounds of formula XXI tion product of formula XXVII in a conventional manner with potassium iodide or an alkali metal carbonate or -bicar- are separated from the reaction mixture. A particularly good example in an organic system containing iodide. A suitable method for the purification consists, for example, of the latter cases. Solvents such as methylene chloride can be used in a concentration of the reaction mixture under reduced pressure. The reaction pressure is preferred, the reaction product of the formula XXVII

temperatures at or below room temperature, especially maintained.

at about 0 ° C. The reaction mixture of the formula XXVII can be

set of sodium sulfate and sodium carbonate are quenched according to the choice of the starting material of the formula XXI as that, whereby an iodine compound of the formula XXII is obtained. 25 primary alcohol, amine or amide obtained. However, if as

If shark stands for a bromine atom, a conventional starting material used is an ester of the formula XXI, added cyclobromating agent N-bromosuccinimide. This usually gives the corresponding alkali metal salt of the solvents, such as methylene chloride, used for the formula XXVII. Such salts can by known requests. The reaction generally takes place in the course of a temperature esterification measure in the esters of the formula XXVIII from about 0 ° C. to room temperature. If the Reak- 30 leads. An easy to carry out process for the production product of the formula XXII in pure form, the corresponding Xx different esters of the formula should be shown, one can isolate the pure form chroma-XXVIII results from Mukaiyama «Chem. Letters », Use the tographic procedure. For such insulation 1045 (1975). According to this process, the alkali can first be dissolved particularly well, the high-pressure liquid chromatograph metal salt of the formula XXVII in dimethylformamide. 35 den, whereupon the mixture obtained at room temperature e.g.

The compounds of formula XXII obtained can be stirred with N-methyl-2-bromopyridinium iodide for several hours, and compounds of formula XXIII are mixed by alkanoylation. Then the alcohol corresponding to the desired ester of the various free hydroxyl radicals of the compounds can be added dissolved in trimethylamine, whereupon the

Get Formula XXII. This alkanoylation is preferred, esterification takes place promptly. After the reaction has ended, at about room temperature in the presence of an amine base, e.g. 40 the desired product in the usual known manner purely of pyridine, and of the alkanoate to be prepared.

corresponding alkane carboxylic acid anhydride. For example, if you prefer to produce a wide variety of pharmaceutical

as the acetates of formula XXIII wants to produce, works macologically acceptable salts of formula XXVIII (apart from acetic anhydride in pyridine. Under the described from the alkali metal salts of formula XXVII), the mild conditions, the alkanoate formation is usually in 45 compounds of the formula XXVlI initially ended by acidification in a few hours to a few days. the free acid is transferred, which is then quickly converted into diethyl ether

It can be extracted from the compounds of the formula XXIII. The ethereal solution obtained in each case can obtain bonds of the formula XXIV by dehydrohalogenation with then with an aqueous solution with the desired salt of a base. For this purpose, the bases corresponding to formula XXVIII are particularly suitable for allowing a wide variety of organic bases to react, e.g. Potassium tert-butoxide 50 become. When the desired neutralization has ended, and l, 5-diazabicyclo- [5.4.0] -undec-5-ene. e.g. the salt of the formula XXVIII in the usual known manner,

The PGI2-like intermediates of formula XXIV, for example by evaporation of the solvent, can then be prepared purely by hydrolysis under mild acidic conditions.

into the corresponding 6-oxo-PGFla-like compounds. The compounds of formula XXI, i.e. the described of the formula XXV are transferred. To carry out the Hy-55 prostaglandin analogs, are either known as such or drolysis reactions are suitable, for example, mixtures of Es- can be prepared by known methods. Examples of acetic acid, tetrahydrofuran and water. Such known compounds and processes for their preparation from the obtained Ge

Mixture of hydrolysis products can then be found in the usual way in US Pat. No. 3,987,072 (11-deoxy-PG-like manner, for example by column chromatography, one compound), 3,950,363 (11-deoxy-ll-hydroxymethylpro -

Product of formula XXV can be isolated. 60 staglandin analogs), 4 026 909 (cis-13-PG compounds),

The respective compound of formula XXV can then be 4 029 618 (13,14-didehydro-PG compounds), 3 728 382

by heating to reflux temperature in benzene or one (15-methyl-PG-like compounds), 3 903 131 (16-methyl

similar monocyclic or bicyclic, essentially prostaglandin analogs), 3,969,380 (16-fluoroprostaglandinan

non-polar aromatic solvent to the 6,7-didehyloge), 3 987 087 (17-phenylprostaglandin analogs), 3 864 387

dro-PGI-like intermediate of formula XXVI recycled (16-phenoxy-PG-like compounds), 4 001 300 (2,2-di-

be settled. The obtained 6,7-didehydro-PGI-like bifluoro-PG-like compounds), 4 028 419 (2-decarboxy-2-hy-

The product of formula XXVI is then usually made from the droxymethyl-PG-like compounds), 3,894,062 (aromatic

Reaction mixture by chromatographic route or according to esters of PG-like compounds), 3 981 868 (amido

638 510

16

and cycloamido derivatives of PG-like compounds) and 3 954 741 (carbonylamido and sulfonylamido-PG-like compounds) and in U.S. Patent Application Serial No. 719,055 (2-decarboxy-2-aminomethyl-PG-like compounds).

The following examples are intended to illustrate the invention in more detail.

All temperature data mean ° C.

The IR (infrared) absorption spectra are recorded using a commercially available infrared spectrophotometer. Unless otherwise stated, undiluted samples are used.

The UV (ultraviolet) spectra are recorded using a commercially available UV spectrophotometer.

The NMR (nuclear magnetic resonance) spectra are recorded using commercially available nuclear magnetic resonance spectrophotometers, using deuterochloroform solutions and tetra-methylsilane as the internal standard (downfield).

The mass spectra are recorded using a commercially available double-setting mass spectrometer with a high resolution or a commercially available gas chromatograph mass spectrometer. Unless otherwise stated, trimethylsilyl derivatives are used.

A “brine” is a saturated aqueous sodium chloride solution.

The A-IX solvent system used in thin layer chromatography consists of ethyl acetate / acetic acid / 2,2,4-trimethylpentane / water in a ratio of 90: 20: 50: 100 (cf. M. Hamberg and B. Samuelsson in «J. Biol. Chem. », Volume 241, page 257 (1966)).

SSB stands for a commercially available mixture of isomeric hexanes.

The term "silica gel chromatography" also includes the elution, collection of fractions and pooling of those fractions which contain the pure product on the basis of thin-layer chromatography studies, i.e. are free of raw materials and contaminants.

The pour points are determined using a Fisher-Johns or Thomas Hoover melting point apparatus.

The specific rotation (a) is determined on the basis of solutions of the compound in question in the specified solvent at room temperature with the aid of a commercially available automatic polarimeter.

example 1

Prostacyclin, diacetate, methyl ester (compound of the formula XXIV, in which: X2 is a radical of the formula -COOCH3; R2 is a hydrogen atom; g = 1; R18 is a radical of the formula -OCOCH3; Y! Trans-CH = CH-; R5 is the radical M5; R3 and R4 of the unit L! Are hydrogen atoms; R12 of the radical M5 is an acetyl radical and R7 is an n-butyl radical):

A. A solution of 5.0 g of 9-deoxy-6,9a-epoxy-5-iodine-PGFj, methyl ester (cf. RA Johnson and co-workers in "JACS", volume 99, page 4182 (1977), compound of the formula XXII) in 25 ml of pyridine and 10 ml of acetic anhydride are kept at room temperature for 4.5 hours, after which ice is added. The diacetate of the formula XXIII is then extracted with ethyl acetate. The organic extracts obtained are washed with water, cold 3N aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated under reduced pressure. The evaporation residue obtained consists of crude intermediate of formula XXIII.

B. The evaporation residue from Part A is dissolved in a small amount of benzene, after which the benzene is removed by evaporation under reduced pressure. 50 ml of dry benzene and 10 ml of 1,5-diazabicyclo [5.4.0] -undec-5-ene are then added, and the mixture obtained is stirred at room temperature for 72 h. After the addition of water, the organic phase is gradually washed with further water and brine, dried over sodium sulfate and concentrated to a residue, namely crude intermediate of For-5 mei XXIV. In silica gel thin-layer chromatography, the Rr value in acetone and methylene chloride (16:84) is 0.83. The pure prostacyclin, diacetate, methyl ester is obtained by silica gel chromatography. The silica gel is packed wet in the column in SSB with 5% triethylamine and prewashed with SSB with 0.1% triethylamine. The eluent consists of 0 to 50% ethyl acetate in SSB with 1/10% triethylamine.

The mass spectrum shows peaks at 450 (molecular ion), 390,363, 359,300,299,259,247,245, 243,143 and 111. 15 Characteristic IR absorptions are found at 1735,1240 and 1695 cm-1. NMR absorptions can be observed at 5.7-5.5, 5.5 and 4.5,4.18,3.67,2.01 and 1.98 ô.

Example 2

20 6-Oxo-PGFla, 11,15-diacetate, methyl ester (compound of the formula XXV, in which X2, R2, g, R18, Yb M4, Lt and R7 have the meaning given in Example 1):

A solution of 499 mg of the reaction product of Example 1 and 5 ml of tetrahydrofuran is diluted with 1.5 ml of water and stirred at a temperature of 25 ° C. for 68 hours. A small amount of acetic acid (approximately 15 drops) is then added and stirring is continued for a further 9 hours. The product of formula XXV thus formed is isolated by first adding ethyl acetate to the reaction mixture and then washing it with saturated sodium bicarbonate solution and brine, drying with sodium sulfate and concentrating to a residue. The residue obtained is chromatographed on 50 g of silica gel using 50 to 100% ethyl acetate in SSB as the eluent. The fractions containing the pure product (405 35 mg) are combined. The R £ value in silica gel thin layer chromatography in ethyl acetate and methylene chloride (16:84) is 0.38. The mass spectrum shows peaks at 480,407,390,347,330,307, 299,259 and 247. Characteristic IR absorptions are observed at 3550.1740 and 1725 cm-1. Characteristic NMR absorptions are found at 4.5-4.2 and 2.8-2.2 ô.

Example 3

6,7-Didehydro-PGIi, diacetate, methyl ester (compound 45 of the formula XXVI, in which Zj is - (CH2) 4— and X2, R, 8, Yl5, M5, Lj and R7 have the meaning given in Example 1):

A solution of 1.09 g of the reaction product of Example 2 in 50 ml of benzene is heated to reflux for about 1.5 hours in the presence of anhydrous magnesium sulfate. Here three different products are obtained. The intermediate product of the heading consists of the least polar product; it shows an Rr value of 55 0.44 in silica gel thin-layer chromatography in ethyl acetate and hexane (1: 3).

500 ml of the crude product mixture obtained are chromatographed on silica gel, using 10 to 20% ethyl acetate in SSB with 0.1% triethylamine as the eluent. From the least polar fractions, 163 mg 60 pure intermediate product of the heading is obtained. The NMR spectrum is characterized by a narrow doublet centered at 4.66 ö. The IR spectrum is characterized by an absorption at 1660 cm -1 (in contrast to the characteristic absorption for prostacyclin at 1695 cm- ').

65

Example 4

6,7-Didehydro-PGIi, sodium salt (compound of the formula XXVII, in which X4 is -COO ~ Na +, for example that in Example 3

17th

638 510

has the meaning given, R8 is a hydroxyl radical and Y1; Mj, Lt and R7 have the meaning given in Example 1):

A solution of 383 mg of the reaction product of Example 3 in 8.5 ml of methanol is treated under a nitrogen atmosphere at a temperature of 25 ° C. with a single equivalent (8.8 ml) of O, In sodium methoxide in methanol for 5 hours. The solution thus obtained is then concentrated under reduced pressure, the methyl acetate by-product being removed. The evaporation residue obtained is redissolved in 8.5 ml of methanol and 1.5 ml of water. The resulting solution is stirred under a nitrogen atmosphere for 12 hours, after which 10 ml of water is added and the methanol is evaporated under reduced pressure. The aqueous solution obtained in this way is freeze-dried, 0.259 g of 6,7-didehydro-PGIb sodium salt being obtained in solid form.

Example 5

6,7-didehydro-PGIi, tris (hydroxymethyl) aminomethane

salt:

The 6,7-didehydro-PGl !, sodium salt of Example 4 is acidified with dilute aqueous hydrochloric acid and quickly extracted from the aqueous solution with diethyl ether. The ethereal solution obtained in this way is combined with stirring with a solution of tris (hydroxymethyl) aminomethane with exactly 1 equivalent of this base. Thereafter, the aqueous solution obtained is purified with the 6,7-didehydro-PGIi, tris (hydroxymethyl) aminomethane salt according to the isolation procedure of Example 4, whereby the pure salt is obtained.

Example 6

6,7-Didehydro-PGIi, methyl ester (compound of the formula XXVIII, in which Xt is a radical of the formula -COOCH3,.

Zj has the meaning given in Example 3, Rg has the meaning given in Example 4 and Y1; Mt, Lt and R7 35 16-phenyl-17,18,19,20-tetranor

According to Example 2, the prostacyclin, diacetate, amide is converted into 6-oxo-PGFla, 11,15-diacetate, amide. Thereafter, the 6-oxo-PGFla-like compound obtained in accordance with Example 3 in 6,7-didehydro-PGI1; Diacetate, 5 amide transferred.

Finally, the 6,7-didehydro-PGIj, diacetate, amide is converted into the 6,7-didehydro-PGIj, amide according to Example 4.

According to the preceding examples, but using suitable PGF2a, 1 l-deoxy-PGF2a or 11-deoxy-1 l-hydroxymethyl-PGF2a-like starting materials are obtained

6,7-didehydro-PGIi-like compounds, ll-deoxy-ó ^ -didehydro-PGIj-like compounds or 15 ll-deoxy-ll-hydroxymethyl-ö ^ -didehydro-PGIi-like compounds, in the form of the amides, Esters or pharmacologically acceptable salts with the following side chain substituents:

15-methyl

16-methyl

20 15,16-dimethyl 16,16-dimethyl

16-fluorine

15-methyl-16-fluorine 16,16-difluoro 25 15-methyl-16,16-difluoro

17-phenyl-18,19,20-trinor

17- (m-trifluoromethylphenyl) -l 8,19,20-trinor 17- (m-chlorophenyl) -18,19,20-trinor 17- (p-fluorophenyl) -18,19,20-trinor 3 o 15 - Methyl-17-pheny 1-18,19,20-trinor 16-methyl-17-phenyl-18,19,20-trinor 16,16 -dimethyl-17 -phenyl-18,19,20-trinor 16-fluoro- 17-phenyl-18,19,20-trinor 16,16-difluoro-17-phenyl-18,19,20-trinor have the meaning given in Example 1):

The 6,7-didehydro-PGl !, sodium salt of Example 4 is dissolved in dimethylformamide and mixed with 1 equivalent of methyl iodide. The resulting mixture is then stirred at room temperature for several hours, after which a thin layer chromatographic analysis on silica gel shows that the esterification reaction has ended. The reaction mixture is then gradually washed with water and brine and concentrated to a residue containing the pure 6,7-didehydro-PGIb methyl ester.

Example 7

6,7-didehydro-PGIi, phenyl ester

The 6,7-didehydro-PGIi, sodium salt of Example 4 is ,,. ". ,

dissolved in dimethylformamide and with stirring with 1 equivalent of e ^ p enoxy,> rinor

15-methyl-16-phenyl-17,18,19,20-tetranor

16- (m-trifluoromethylphenyl) -l 7,18,19,20-tetranor 16- (m-chlorophenyl) -17,18,19,20-tetranor 16- (p-fluorophenyl) -l 7,18,19, 20-tetranor 16-phenyl-18,19,20-trinor 15-methyl-16-phenyl-18,19,20-trinor 16-methyl-16-phenyl-18,19,20-trinor 15,16-dimethyl- l 6-phenyl-l 8,19,20-trinor 16-phenoxy-17,18,19,20-tetranor

45 15 -methyl-16-phenoxy-17,18,19,20-tetranor

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor 16- (m-chlorophenoxy) -17,18,19,20-tetranor 16- (p-fluorophenoxy) -17,18,19,20- tetranor 16-phenoxy-18,19,20-trinor

N-methyl-2-bromopyridium iodide added. After several hours, the mixture obtained is combined with 1 equivalent of phenol in triethylamine and the reaction mixture is stirred at room temperature for several hours. After a thin-layer chromatographic analysis on silica gel has shown that the esterification reaction has ended, the pure 6,7-didehydro-PGIj, phenyl ester is obtained by the purification process according to Example 6.

Example 8 6,7-Didehydro-PGIi, Amide:

According to R.A. Johnson and co-workers in "J.A.C.S.", volume 99, page 4182 (1977), but using PGF2u, amide instead of PGF2a or PGF2a, methyl ester gives 9-deoxy-6,9a-epoxy-PGFla, amide. Furthermore, 9-deoxy-6,9a-epoxy-PGF1; Amide according to Example 1 prostacyclin, diacetate, amide.

16-methyl-16-phenoxy-18,19,20-trinor 15,16-dimethyl-l 6-phenoxy-18,19,20-trinor 13,14-didehydro 16-methyl-13,14-didehydro 55 16, 16-dimethyl-13,14-didehydro

16-fluoro-13,14-didehydro

16,16-difluoro-13, 14-didehydro

17-phenyl-18,19,20-trinor-13,14-didehydro 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-didehydro

60 17- (m-chlorophenyl) -l 8,19,20-trinor-l 3,14-didehydro 17- (p-fluorophenyl) -18,19,20-trinor-13,14-didehydro 16-methyl-17 -phenyl-18,19,20-trinor-13,14-didehydro 16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro 16-fluoro-17-phenyl-18,19 , 20-trinor-13,14-didehydro 65 16,16 -dif luor-17 -phenyl- 18,19,20-trinor-13, l 4-didehydro 16-phenyl-17,18, l 9.2 0- tetranor-13,14-didehydro 16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14-di-dehydro

638 510

18th

16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-didehydro 16-phenyl-l 8,19,20-trinor-l 3,14-didehydro 16-methyl-16-phenyl- 18,19,20-trinor-13,14-didehydro 16-phenoxy-17,18,19,20-tetranor-13,14-didehydro 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor- 13,14-didehydro

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-

16-phenoxy-18,19,20-trinor-13,1 4-didehydro

16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-

13,14-dihydro

16-methyl-13,14-dihydro

16,16-dimethyl-l 3,14-dihydro

16-fluoro-l 3,14-dihydro 16,16-difluoro-13, l 4-dihydro

17-phenyl-18,19,20-trinor-13,14-dihydro 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro 17- (m-chlorophenyl) -18,19, 20-trinor-13,14-dihydro

17- (p-fluorophenyl) -1,1,19,20-trinor-13,14-dihydro 16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro 16,16-dimethyl-17 -phenyl-18,19,20-trinor-13,14-dihydro 16-fluoro-17 -phenyl-18,19,20-trinor-13,14-dihydro 16,16-difluoro-17-phenyl-18,19 , 20-trinor-13,14-dihydro 16-phenyl-17,18,19,20-tetranor-13,14-dihydro 16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13,14 -di-hydro

16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-dihydro 16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro 16-phenyl- l 8,19,20-trinor-l 3,14-dihydro 16-methyl-16-phenyl-18,19,10-trinor-13,14-dihydro 16-phenoxy-17,18,19,20-tetranor- 13,14-dihydro 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro 16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro 16-phenoxy- l 8,19,20-trinor-l 3,14-dihydro 16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro 13-cis

16-methyl-13-cis 16,16-dimethyl-13-cis

16-fluoro-13-cis 16,16-difluoro-13-cis

17-phenyl-18,19,20-trinor-13-cis

17- (m-trifluoromethylphenyl) -18,19,20-trinor-13-cis 17- (m-chlorophenyl) -18,19,20-trinor-13-cis 17- (p-huorphenyl) -18.19, 20-trinor-13-cis

16-methyl-17-phenyl-18,19,20-trinor-13-cis

16,16-dimethyl-17-phenyl-18,19,20-trinor-13-ice

16-fluoro-l 7-phenyl-l 8,19,20-trinor-l 3-cis

16,16-difluoro-17-phenyl-18,19,20-trinor-l 3-ice

16-phenyl-17,18,19,20-tetranor-l 3 ice

16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor-13-cis

16- (m-chlorophenyl) -17,18,19,20-tetranor-13-cis

16- (p-fluorophenyl) -17,18,19,20-tetranor-13-cis

16-phenyl-18,19,20-trinor-13-cis

16-methyl-16-phenyl-18,19,20-trinor-13-cis

16-phenoxy-l 7,18,19,20-tetranor-l 3-cis

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13-cis

16- (m-chlorophenoxy) -17,18,19,20-tetranor-l 3-cis

16- (p-fluorophenoxy) -l 7,18,19,20-tetranor-13-ice

16-phenoxy-l 8,19,20-trinor-l 3-cis

16-methyl-16-phenoxy-l 8,19,20-trinor-13-ice

2,2-difluoro

2,2-difluoro-15 methyl

2,2-difluoro-1 6-methyl

2,2-difluoro-16,16-dimethyl

2,2-difluoro-l 6-fluor

2,2-difluoro-16,16-difluoro

2,2-difluoro-l 7-phenyl-l 8,19,20-trinor

2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor 2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor 2,2-difluoro-16-methyl-l 7-phenyl-18,19,20-trinor 5 2,2-difluoro-16,16-dimethyl-17- phenyl-18,19,20-trinor 2,2-difluoro-16-fluoro-17-phenyl-18,19,20-trinor 2,2-difluoro-16,16-difluoro-17-phenyl-18,19, 20-trinor 2,2-difluoro-16-phenyl-17,18,19,20-tetranor 2,2-difluoro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetranor io 2,2- Difluoro-16- (m-chlorophenyl) -17,18,19,20-tetranor 2,2-difluoro-16- (p-fluorophenyl) -17,18,19,20-tetranor 2,2-difluoro-16- phenyl-18,19,20-trinor 2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor 2,2-difluoro-16-phenoxy-17,18,19,20-tetranor 15 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-nor

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor 2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor 2,2- Difhior-16-phenoxy-18,19,20-trinor 20 2,2-difluoro-l 6-methyl-l 6-phenoxy-18,19,20-trinor 2,2-difluoro-16-methyl-13,14 -didehydro 2,2-difluoro-16,16-dimethyl-13,14-didehydro 2,2-difluoro-16-fluoro-13,14-didehydro 2,2-difluoro-16,16-difluoro-13,14 -didehydro 25 2,2-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro 2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13, 14-didehydro

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dide-hydro

30 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-didehy-dro

2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dide-hydro

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-35 didehydro

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-13,14 -didehydro

2,2-difluoro-16-phenyl-17,18,19,20-tetranor-13,14-didehydro 40 2,2-difluoro-16- (m-trifluoromethylphenyl) -17,18,19,20-tetra- nor-13,14-didehydro

2,2-difluoro-16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-didehydro

2,2-difluoro-16-phenyl-18,19,20-trinor-13,14-didehydro 45 2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-13,14- dide-hydro

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-50 nor-13,14-didehydro

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro

2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-didehydro 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-di -55 dehydro

2,2-difluoro-13,14-dihydro 2,2-difluoro-16-methyl-13,14-dihydro 2,2-difluoro-16,16-dimethyl-13,14-dihydro 2,2,16-trifluoro -13,14-dihydro 60 2,2,16,16-tetrafluoro-13,14-dihydro 2,2-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro 2,2-difluoro -17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihy-65 dro

2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro 2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13 , 14-dihy-dro

19th

638 510

2,2-difluoro-l 6,16-dimethyl-17-phenyl-l 8,19,20-trinor-13,14-dihydro

2,2,16-trifluoro-l 7-phenyl-l 8,19,20-trinor-l 3,14-dihydro 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor- 13,14-dihydro 2,2-difluoro-l 6-phenyl-l 7,18,19,20-tetranor-l 3,14-dihydro 2,2-difluoro-16- (m-trifluoromethylphenyl) -17.18 , 19,20-tetranor-13,14-dihydro

2,2-difluoro-16- (m-chlorophenyl) -17,18,19,20-tetranor-13,14-dihydro

2,2-difluoro-16- (p-fluorophenyl) -17,18,19,20-tetranor-13,14-dihydro

2,2-difluoro-16-phenyl-16-phenyl-18,19,20-trinor-13,14-dihydro

2,2-D if luor-16-methyl 1-16-phenyl-18,19,20-trinor-13,14-dihydro

2,2-difluoro-16-phenoxy-l 7,18,19,20-tetranor-l 3,14-dihydro 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra -nor-13,14-dihydro

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro

2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13,14-di-hydro

2,2-difluoro-13-cis 2,2-difluoro-l 6-methyl-l 3-cis 2,2-difluoro-l 6,16-dimethyl-l 3-cis 2,2,16-trifluoro-l 3-cis

2,2,16,16-tetrafluoro-13-ice 2,2-difluoro-17-phenyl-18,19,20-trinor-13-cis 2,2-difluoro-l 7- (m-trifluoromethylphenyl) - 18,19,20-trinor-13-cis

5 2,2-difluoro-17- (m-chlorophenyl) -l8,19,20-trinor-l3-ice 2,2-difhior-17- (m-fluorophenyl) -18,19,20-trinor-13- cis 2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13-cis 2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor- 13-cis 2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13-cis io2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-13- cis 2,2-difluoro-16-phenyl-17,18,19,20-tetranor-13-cis 2,2-difluoro-l 6- (m-trifluoromethylphenyl) -17,18,19,20-tetra-nor -13-cis

2,2-difluoro-l 6- (m-chlorophenyl) -17,18,19,20-tetranor-13-cis 15 2,2-difluoro- (p-fluorophenyl) -17,18,19,20-tetranor -13-cis 2,2-difluoro-l 6-phenyl-18,19,20-trinor-l 3-cis 2,2-difluoro-16-methyl-16-phenyl-18,19,20-trinor-13 -cis 2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13-cis 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-2onor -13-cis

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-cis 2,2-difluoro-l 6- (p-fluorophenoxy) -l 7,18,19,20 -tetranor-13-cis 2,2-difluoro-16-phenoxy-18,19,20-trinor-13-cis and 2,2-difluoro-16-methyl-l 6-phenoxy-18,19,20-trinor- 13-cis. 25 Using other suitable 2-decarboxy-2-hydroxymethyl or -2-aminomethyl starting materials, the corresponding products of the various carboxylate prostacyclin analogues described are obtained.

C.

Claims (2)

638 510 2 PATENT CLAIMS 1. Prostacyclin analogues of the formula: Zj-Xj means an acetamido residue, a substituted phenyl residue, a phenacyl residue, i.e. a radical of the formula: 0 o -ch2-c / \, a phenacyl radical substituted in the p-position by chlorine Y, -C —C-R7 h i M5 L, (vii) io or bromine or the phenyl or benzamido radical; O where: Z! (1) - (CH2) g- (CH2) 2-CH2- or (2) - (CH2) g- (CH2) 2-CF2-, where g = 1,2 or 3; Rlg is hydrogen, an alkanoyloxy radical having 2 to 8 carbon atoms or an alkanoyloxymethyl radical having 2 to 8 carbon atoms; Yi (1) trans-CH = CH-, (2) cis-CH = CH, (3) -CH2CH2- or (4) -C = C; m, R5 OR12 or R5 OR12, wherein R5 represents hydrogen or the methyl radical and R12 represents an alkanoyl radical having 2 to 8 carbon atoms; R3 R4 or a mixture of li r, r4 \ R3 R4 and R3 R4, in which R3 and R4, which may be the same or different, can represent hydrogen, fluorine or methyl radicals, with the proviso that one of the radicals R3 and R4 only means fluorine when the other is hydrogen or fluorine; X2 (1) is a radical of the formula -COOR2, in which R2 is an alkyl radical with 1 to 12 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, the phenyl radical, one with 1, 2 or 3 Chlorine atoms or alkyl radicals with 1 to 3 carbon atoms substituted phenyl radical, a in the p-position by a radical of the formulas: O II (a) -NH-CR25 O (b) -OCR; (2) a radical of the formula -CH2OC-CpH2p-CH3, in which 15 p = 0.1,2, 3,4,5 or 6, (3) a radical of the formula -CH2NL2L3, in which L2 and L3 are hydrogen or alkyl radicals with 1 to 4 carbon atoms, or (4) a radical of the formula -COL4, in which L4 20 (a) an amino radical of the formula -NR21R22, in which R21 and R22 are (1) hydrogen, (2) alkyl radicals with 1 to 12 carbon atoms, (3) cycloalkyl radicals with 3 to 10 carbon atoms, 65 (4) aralkyl radicals with 7 to 12 carbon atoms, (5) phenyl, (6) with 1, 2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxyl radicals, carboxy radicals, alkoxycar- 638 510 4th bonyl residues with 1 to 4 carbon atoms or nitro residues substituted phenyl residues, (7) carboxyalkyl radicals having 1 to 4 carbon atoms, (8) carbamoylalkyl radicals having 1 to 4 carbon atoms, (9) cyanoalkyl radicals with 1 to 4 carbon atoms, (10) acetylalkyl radicals with 1 to 4 carbon atoms, (11) benzoylalkyl radicals with 1 to 4 carbon atoms, (12) benzoylalkyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals, alkoxy radicals with 1 to 3 carbon atoms, carboxy radicals, alkoxycarbonyl radicals with 1 to 4 carbon atoms or nitro radicals, (13) pyridyl residues, (14) pyridyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms, (15) pyridylalkyl radicals having 1 to 4 carbon atoms, (16) pyridylalkyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals or alkoxy radicals with 1 to 3 carbon atoms, (17) hydroxyalkyl residues with 1 to 4 carbon atoms, (18) Dihydroxyalkyl radicals with 1 to 4 carbon atoms or (19) trihydroxyalkyl radicals having 1 to 4 carbon atoms, with the further proviso that at most one of the radicals R2i and R22 represents a radical other than hydrogen or an alkyl radical, (b) a cycloamino radical of the formulas: R7 (1) - (CH2) m-CH3, in which mean: 15 m is an integer from 1 to 5; h 0 or 1 to 3; s 0,1,2 or 3 and T is chlorine or fluorine or the trifluoromethyl group, alkyl having 1 to 3 carbon atoms or alkoxy radical having 1 to 3 20 carbon atoms, with the proviso that at most two radicals T stand for radicals other than alkyl radicals, and where Rs represents hydrogen, hydroxyl or hydroxymethyl . 4. Prostaglandin analogs according to claim 3, characterized in that R8 is hydrogen. 25 5. Prostaglandin analogues according to claim 4, characterized in that Yj means trans-CH = CH-. 6. prostaglandin analog 6,7-didehydro-PGI1-methyl ester according to claim 5. 7. prostaglandin analogue 6,7-didehydro-PGI1-tris (hydr-30 oxymethyl) aminomethane according to claim 5. 8. Prostaglandin analog 6,7-didehydro-PGIi-Adaman-tanamine salt according to claim 5. 9. Prostaglandin analog 6,7-didehydro-PGIp sodium salt according to claim 5. - \ ^ JL l22 or -et 21st * 2 2 ■ G ( 2 1 (1) hydrogen, (2) alkyl radicals with 1 to 12 carbon atoms, (3) cycloalkyl radicals with 3 to 10 carbon atoms, 25 (4) aralkyl radicals with 7 to 12 carbon atoms, (5) phenyl residues, (6) with 1, 2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxyl radicals, carboxy radicals, alkoxycarbonyl radicals with 1 to 4 carbon atoms or nitro radicals 30 substituted phenyl radicals, (7) carboxyalkyl radicals having 1 to 4 carbon atoms, (8) carbamoylalkyl radicals having 1 to 4 carbon atoms, (9) cyanoalkyl radicals with 1 to 4 carbon atoms, (10) acetylalkyl radicals with 1 to 4 carbon atoms, 35 (11) benzoylalkyl radicals with 1 to 4 carbon atoms, (12) with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals, alkoxy radicals with 1 to 3 carbon atoms, carboxy radicals, alkoxycarbonyl radicals with 1 to 4 carbon atoms or nitro radicals 40 coylalkyl residues, (13) pyridyl residues, (14) pyridyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms, 45 (15) pyridylalkyl radicals with 1 to 4 carbon atoms, (16) pyridylalkyl radicals substituted with 1,2 or 3 chlorine atoms, alkyl radicals with 1 to 3 carbon atoms, hydroxy radicals or alkoxy radicals with 1 to 3 carbon atoms, (17) hydroxyalkyl radicals having 1 to 4 carbon atoms, so (18) dihydroxyalkyl radicals having 1 to 4 carbon atoms or (19) trihydroxyalkyl radicals having 1 to 4 carbon atoms, with the further proviso that no more than one of the radicals R21 and R22 is different from hydrogen or alkyl, (b) a cycloamino radical Formulas: 26 55 O (c) -O-C for \ R, 7 or -3C O (d) -CH = N-NHC-NH2 wherein R25 represents the methyl, phenyl, acetamidophenyl, benzamido-dophenyl or -NH2 radical, R26 represents the methyl, phenyl, —NH2— or methoxy radical and R27 is hydrogen or 65 3rd 638 510 -N NO * 21 * 22 or in which R2i and R22 have the direction indicated above, (c) a carbonylamino radical of the formula —NR23COR21, in which R23 represents hydrogen or an alkyl radical having 1 to 4 carbon atoms and R21 has the meaning given above, (d) a sulfonylamino radical of the formula -NR23S02R2i, in which R2i and R23 have the meaning given above, or (e) a hydrazine radical of the formula -NR23R24, in which R23 has the meaning given above and R24 stands for an amino radical of the formula -NR21R22 as defined above or a cycloamino radical as defined above, and R7 (1) - (CH2) ra-CH3, (2) - (CH2) h (3) -O // (T) s or (T) s X Z, -Xi Y 1 - Ç C - R 7 il H »! h where: Zt (1) - (CH2) g- (CH2) 2-CH2- or (2) - (CH2) g- (CH2) 2-CF2-, where g = 1, 2 or 3; Yj (1) trans-CH = CH- (2) cis-CH-CH, (3) -CH2CH2- or (4) -oc; / \ ✓ 's R5 OH or Rs OH, 5 wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms; / \ ^ Lj R3 R4, R3 R4 or a mixture of R3 R4 and R3 R4, wherein R3 and R4, which may be the same or different, may represent hydrogen or fluorine or methyl radicals, with the proviso that one of the radicals R3 and R4 means fluorine only when the other represents hydrogen or fluorine; X1 (1) is a radical of the formula -COOR10, in which R10 is hydrogen, an alkyl radical with 1 to 12 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical, 20 one with 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms substituted phenyl radical, one in the p-position by a radical of the formulas: 25th in which mean: m is an integer from 1 to 5; h 0 or Ibis 3; sO, 1,2 or 3 and T is a chlorine or fluorine or the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms, with the proviso that at most two radicals T stand for radicals other than alkyl radicals. 2,6,7-didehydro-PGlrmethyl ester, diacetate according to claim 1. 3. Prostacyclin analogs of the formula 35 40 O II (a) -NH-CR25 O II (b) -o-c-R26 o (c) -O-C - R27 or O II (d) -CH = N-NHC-NH2 45 wherein R25 represents the methyl, phenyl, acetamidophenyl, benzamido-dophenyl or -NH2 radical, R26 represents the methyl, phenyl, -NH2 or methoxy radical and R27 represents hydrogen or the acetamido radical, a phenacyl radical , ie a remainder of the formula: O CH2-C, one in the p-position by chlorine 50 or bromine or the phenacyl or benzamido substituted phenacyl group, or a pharmacologically acceptable cation; 55 (2) the rest of the formula -CH2OH, (3) a radical of the formula -CH2NL2L3, in which L2 and L3 represent hydrogen or alkyl radicals having 1 to 4 carbon atoms, or (4) a radical of the formula -COL4, in which L4 (a) is a 6o amino radical of the formula -NR21R22, in which R21 and R22 for '2 2